Syk, a non-receptor tyrosine kinase constituting the Syk family with ZAP70, is expressed in a wide range of immune-related cells including B cells, macrophages, neutrophils, and mast cells and involved in their functions. Syk binds to the ITAM domains of immunoreceptors such as Fc receptor family (FcR) or B cell receptor (BCR) expressed in these cells and plays a role in transducing downstream signals from these receptors. In B cells, Syk is activated by BCR after antigen stimulation. The activated Syk activates various downstream signaling pathways such as PI3K, Ca2+-NFAT, and RAS-MAPK pathways and finally plays an important role in B cell activation, differentiation, and maturation.
In recent years, it has become increasingly evident that these B cell receptor signals and Syk functions play an important role in the growth or survival of B cell-derived blood cancer such as B cell lymphoma or chronic lymphatic leukemia (CLL). Specifically, the B cell receptor signals in diffuse large B cell lymphoma (DLBCL) are chronically activated in an antigen-independent manner, and the activated signals are essential for the growth or survival of cancer cells (Non Patent Document 1). The high expression or activation of Syk reportedly plays an important role in the survival of CLL (Non Patent Document 2). According to the further reports, the treatment of these blood cancer cells with compounds having a Syk inhibitory effect is effective for inhibiting their growth or inducing cell death (Non Patent Documents 1 and 2). Thus, from these pieces of information, the inhibition of Syk is expected to produce therapeutic effects on B cell lymphoma or CLL. Also, it has been suggested that Syk is involved in malignant transformation to peripheral T cell lymphoma (PTCL), myelodysplastic syndrome (MDS), and blood cancer of origin other than B cells, such as acute myeloid leukemia (AML). Accordingly, Syk inhibitors are expected to be able to serve as therapeutic agents effective not only for B cell-derived cancer but for T cell lymphoma or AML.
The Syk inhibitors have also been reported to be able to serve as therapeutic agents for cancer as well as autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome, etc.), allergic diseases (bronchial asthma, allergic rhinitis, atopic dermatitis, contact dermatitis, urticaria, food allergy, conjunctivitis, etc.), chronic obstructive pulmonary disease (COPD), and the like (Non Patent Document 3).
R406 (Rigel Pharmaceuticals, Inc.), which is a Syk inhibitor currently under development (Non Patent Document 4), has low selectivity for Syk and reportedly has adverse effects attributed to its inhibition of kinases other than Syk (Non Patent Document 5).
Heteroaromatic carboxamide derivatives have also been reported as other Syk inhibitors (Patent Document 1) and however, still have insufficient Syk inhibitory activity. Alternatively, Patent Document 2 has reported 1,2,4-triazine-6-carboxamide derivatives and however, has no mention about Syk inhibitory activity.